Matrix for sustained, invariant and independent release of active compounds

ABSTRACT

The invention concerns a storage stable pharmaceutical formulation comprising preferably two active compounds in a non-swellable diffusion matrix, whereby the compounds are released from the matrix in a sustained, invariant and, if several compounds are present, independent manner and the matrix is determined with respect to its substantial release characteristics by ethylcellulose and at least one fatty alcohol. The invention also concerns methods for producing such pharmaceutical formulations.

The invention concerns a storage stable pharmaceutical formulationcomprising at least one pharmaceutically active compound in asubstantially non-swellable diffusion matrix, wherein the compound isreleased from the matrix in a sustained and invariant, and where severalcompounds are present, an independent manner. With respect to itsessential release characteristics the matrix is formed by amounts ofethylcellulose and at least one fatty alcohol.

The invention also concerns a method for producing storage stablepharmaceutical formulations comprising at least one pharmaceuticallyactive compound in a non-swellable diffusion matrix, wherein the atleast one compound is released from the matrix in a sustained andinvariant manner and, where several compounds are present, also anindependent manner.

Sustained release formulations of pharmaceutical preparations take acentral role in the development of improved therapies. It is the intentof all sustained release preparations to provide a longer period ofpharmacological response after the administration of the drug than isordinarily experienced after the administration of rapid release dosageforms. Sustained release pharmaceutical preparations comprisingrelatively large amounts of the pharmaceutically active compound andthat release the compounds in a controlled, regulated manner over alonger period of time (typically 2-16 hours), ensure that the frequencywith which the medicine has to be taken by the patient is reduced andthat higher compliance by the patients is achieved.

The longer release duration and the concomitant prolonged effect of theactive compounds, as is ensured by sustained release pharmaceuticalpreparations, provides moreover for many therapeutic benefits that arenot achieved with corresponding short-acting, immediate releasepreparations. By using sustained release pharmaceutical preparations,therapy may be continued e.g. overnight without the necessity tointerrupt the patient's sleep. This plays a role, for instance, in thetreatment of epilepsy patients, where the occurrence of nocturnalattacks may thus be prevented. In the same way, patients suffering fromchronic pain are allowed undisturbed sleep.

From the medical-pharmacological point of view, one advantage ofsustained release formulations is the very uniform active compoundconcentration in the blood, leading to a long-lasting effect and reducedside effects. The reduction of side effects plays a decisive roleduring, e.g. the use of opioids for pain therapy. Opioid-inducedside-effects comprise among others the danger of an addictiondeveloping. As the addictive potential of an active compound is notdefined by the compound itself, but rather by the way it is administeredand the pharmaco-dynamic resulting therefrom (e.g. by the rate at whichthe brain encounters an active compound), the sustained release of anopioid analgesic can reduce the addictive potential of these activecompounds (Nolte, T.: STK-Zeitschrift für angewandte Schmerztherapie,2001, Vol. 2).

Since sustained release formulations allow for a uniformly high activecompound concentration in the blood, the bio-availability of the activecompound is increased. A multitude of factors contribute to thebio-availability of an active compound. Such factors include the activecompound concentration in the respective physiological fluid (e.g. inthe blood), the absorbability of the active compound across membranes(e.g. for the re-absorption in the gastro-intestinal system) and theavailability of the active compound at the desired tissue site.

In order to be absorbed, for instance by the intestinal system, anactive compound must be in solution. The time required for a givenproportion of an active compound present in a unit dosage of apharmaceutical preparation in order to be dissolved in the respectivephysiological fluid, is designated as the dissolution time, also as therelease time, or release rate. The dissolution time of an activecompound is determined as the proportion of the active compound releasedfrom a unit dosage form over a specified time based on a test methodconducted under standardized conditions. The physiological fluid inwhich the dissolution time of the active compound is determined may be,e.g. the fluid of the gastro-intestinal system. The state of the artrecognises may satisfactory test procedures for measuring dissolutiontime for pharmaceutical compositions (and correspondingly, for therelease rates of the active compounds), and these test procedures aredescribed in official compendia worldwide.

Among the various factors affecting dissolution time of pharmaceuticalcompositions, and thereby the release rates of active compounds, are thesurface area of the pharmaceutical composition accessible to thedissolution solvent medium, the pH of the dissolution solvent medium,the solubility of the active compound in the dissolution solvent mediumand the saturation concentration of dissolved materials in thedissolution solvent medium.

Despite the diverse factors that influence the dissolution of the activecompound in the dissolution medium as well as the absorption of theactive compound, a strong correlation has been established between thein vitro dissolution time determined for a pharmaceutical preparationand the in vivo bio-availability of the active compound. Thiscorrelation is so well established that the dissolution time (releaserate of the active compound) is considered to be a generally acceptedcriterion for the bio-availability of the active compound of apharmaceutical preparation. In view of this correlation, it becomesclear that the release rate as determined for the active compound of apharmaceutical formulation is one of the important fundamentalcharacteristics that has to be considered when evaluating sustainedrelease formulations.

Different approaches are known from the prior art that allow theformulation of sustained release pharmaceutical preparations. Theseapproaches have in common that the active compound is combined withadditives to shape bodies, such as tablets or dragées, with theadditives forming a release or dissolution barrier for the activecompound. Depending on the nature of the release barriers, differentsustained release methods can be distinguished. There are, e.g. osmoticsystems, systems by which retardation is achieved through coatings, orsystems in which the active compounds are embedded in waxes,polymethacrylates, gel-formers or silicic acids. There are moreover theso-called matrix forms, which are of fundamental importance whenformulating sustained release pharmaceutical preparations. Matrix meansa shaped body comprising the active compound bound to additives whichare as inert as possible. Depending on the type of matrix, one candifferentiate between e.g. swellable or non-swellable matrices. Moreovermatrices differ depending on whether the active compound is released bypure diffusion or by erosion of the matrix (U. Schöffling,Arzneiformenlehre, 1998, 3^(rd) edition, Deutscher Apotheker-Verlag,Stuttgart).

The additives used for the preparation of sustained releasepharmaceutical preparations frequently lead to problems concerning thestability of the pharmaceutical preparation after prolonged storagetimes. For e.g. waxes, it has been shown that they are subject tochanges, so that extensive precautionary steps have to be taken even atthe time of production, in order to prevent changes during the storagetime. If film coatings consisting of polymers produced from aqueousdispersions are used for retardation, these pharmaceutical preparationsalso frequently display problems with storage stability.

There are prior art sustained release pharmaceutical preparations havingso-called controlled release of the pharmaceutically active compound,i.e. the release of the active compound is not only prolonged, butmoreover can be adjusted to a predetermined release rate. Depending onwhich polymers (hydroxyalkylcelluloses, polymethacrylates or e.g.alkylcelluloses) are used for the production of e.g. matrix-basedsustained release pharmaceutical preparations with controlled release,the release behaviour of the respective pharmaceutically activecompounds may differ, the release behaviour of the active compoundfrequently being difficult to predict.

Generally, it should be ensured that pharmaceutical preparations of agiven pharmaceutical formulation release the respective compound alwayswith reproducible equal release rates or release profiles, even if theformulation comprises different absolute amounts of the activecompounds. However, due to the stability problems, which are caused bythe components responsible for the sustained release, this is notguaranteed.

There is a large number of sustained release pharmaceutical preparationsfor different therapeutic applications that frequently contain only oneactive compound. The medicament Oxygesic®, which is used in paintherapy, contains e.g. oxycodone as the only analgetically activecompound. The medicament Kapanol®, which is also used in pain therapy,comprises morphine sulfate as analgetically active compound.

As the long term application opioid analgesics such as oxycodone may goalong with the development of side effects such as breath depression andobstipation, co-treatment of patients with opioid antagonists thatspecifically counteract the opioid-induced side effects may benecessary. If patients seeking pain release are treated withpreparations comprising an opioid analgesic, simultaneous treatment withpreparations comprising antagonists such as naltrexone or naloxone maybe desirable in order to counteract the aforementioned side effects. Ifthe opioid-containing preparation is a sustained release preparation,the antagonist-preparation should also provide for a sustained releaseas otherwise development of side effects may not effectively berepressed. However, sustained release formulations of e.g. naloxonealone are not available on the market.

In the treatment of different symptoms it is therefore a common strategyto counteract the side-effects provoked by an active compound bysimultaneous administration of another compound that selectively reducesthese side-effects. If e.g. opioid analgesics are used in pain therapy,side-effects such as obstipation and breath depression may occur inaddition to the danger of the development of dependency and addiction asalready mentioned. Various attempts have therefore been made toeliminate, or at least significantly reduce, the addictive andhabit-forming potential of opioid analgesics as well as their otherside-effects, by the simultaneous administration of antagonists whichcounteract the opioid analgesic.

In view of the significant advantages that such combination preparationshave and due to the aforementioned general advantages of sustainedrelease pharmaceutical preparations, there is a great need for sustainedrelease formulations of such combination preparations. Sustained releaseformulations of combination preparations should combine in an idealmanner the positive, synergistic effects of the different activecompounds with the long-lasting release and the correspondinglyincreased period of effectiveness.

One example of such a combination preparation which releases severalcompounds in a sustained manner is Valoron® from Gödecke, whichcomprises tilidine as an analgetically active compound and naloxone asantagonist.

However, one problem that frequently occurs with combinationpreparations is that active compounds of different chemical structuresand physical characteristics have to be combined in one matrix. Such acombination usually leads to different release profiles for bothcompounds. The release of both compounds with the same release profilescan, however, be highly desirable from a medical point of view.Moreover, it may be preferable that both compounds are released from thesame matrix, since in this way e.g. tablets may be produced which can besplit. Such tablets are suitable for individual dosing and theproduction process of the corresponding preparations can besignificantly simplified. Another aspect is that with several compoundsof different structures being present, the compounds may differ withrespect to their stability in the matrix over a longer storage period.Additionally, the change of amount of one compound may change therelease profile of other compounds in an unpredictable manner in suchcombination preparations, resulting in significant expenditure in theproduction of preparations having different amounts of the activecompounds, since one cannot infer from the release behaviour of onepreparation the release behaviour of another one.

Generally, medicaments have to be formulated in a such a way that theactive compounds are stable as long as possible under standard storageconditions. Medicaments also have to be formulation in such a way thatthe intended release profiles of the active compounds do not changeduring long-term storage.

It should also be ensured that the release profile of one activecompound of a given sustained release formulation does not changedepending on the amount of the active compound. This applies to the casewhere a single compound or also several compounds are present in thepharmaceutical preparation.

Additionally (also in the case of active compound combinations), therelease profile of each single compound should be selectable asrequired. The measures to be taken in order to achieve this should notprevent, or even hamper the release profiles of additional activecompounds, e.g. in the case of combinations of different activecompounds, being chosen as required. Consequently, there should be nomutual dependency of the release profiles.

For a variety of therapeutic applications there is a great need forcombination preparations. Particularly for pain therapy combinationpreparations are required that consist of opioid analgesics andcorresponding antagonists, where the respective pharmaceuticalpreparations release both compounds in a sustained manner and alsopossess the aforementioned characteristics. Matrix formulations thatensure a sustained release of active compounds in general and of opioidanalgesics and their antagonists in particular and that possess theaforementioned characteristics are not known from prior art.

German patent application DE 43 25 465 A1 concerns the treatment ofside-effects during pain therapy by a preparation consisting of anopioid agonist and an antagonist. The characterizing feature of thisdisclosure is that the antagonist must not be released in a sustainedmanner while the agonist should be released in a sustained manner.

International patent application WO 99/32120 is also concerned with apreparation consisting of an opioid analgesic and an antagonist.According to this disclosure, both compounds should be released in asustained manner. Storage stability and the mutual dependency of therelease profiles of compounds is, however, not subject matter of thisapplication.

The aforementioned pain-relief medicament Valoron® is atilidine/naloxone-combination. According to the manufacturer's data itis a formulation from which both active compounds are released in asustained manner. The matrix used comprises a relevant part ofwater-swellable material hydroxypropylmethylcellulose (HPMC)) and hastherefore to be considered as a swellable (and possibly partiallyerosive) diffusion matrix. The disadvantage of this known formulation isthat tilidine and naloxone, given identical mass ratios but differentabsolute amounts, display different release profiles, if the release ismeasured for certain pH values. The release rates of the agonist and theantagonist are not independent of each other, which is probably due tothe sustained release formulation used. Accordingly, it is necessary forthe physician to carry out extensive titration experiments for eachindividual patient if he wants to increase the dosage, even though hedoes not change the mass ratio of tilidine:naloxone, since he cannotassume that the release profiles of both components will remainconstant. The range of therapeutically usable amounts of the analgesicavailable to the physician is therefore limited.

One objective of the present invention is to provide formulations for apharmaceutical preparation that ensure that the active compounds of thepreparations are released in a sustained manner, that are stable over along storage period, and where the release of one compound does notchange even when different amounts of the active compound are used. Afurther objective of the invention is to provide formulations forpharmaceutical preparations that display the above-mentionedcharacteristics and that show no mutual dependency of the releaseprofiles of the active compounds.

Another objective of the present invention is to provide methods forproducing pharmaceutical formulations comprising at least onepharmaceutically active compound and from which the compounds arereleased in a sustained, reproducibly invariant and, where severalcompounds are present, independent manner. Such formulations shouldremain stable even after longer storage periods.

A particular objective of the present invention is to provideformulations for pharmaceutical preparations that comprise the opioidantagonist naloxone, wherein the active compound is stable over a longstorage time and is released from the preparation in a sustained andreproducibly invariant manner. Formulations that achieve this, are notknown from prior art.

An additional objective of the present invention is to provideformulations for pharmaceutical preparations for pain therapy comprisingat least one opioid analgesic and at least one antagonist counteractingthe opioid analgesic, wherein the formulation is stable over a longstorage period and wherein the active compounds are released from thepreparation independently of each other in a sustained and reproduciblyinvariant manner.

The features of the independent claims serve to attain these and further objectives which can be noted from the following description ofthe invention. Preferred embodiments of the invention are defined in thedependent claims.

According to the invention the objectives are solved by providing apharmaceutical formulation comprising at least one pharmaceuticallyactive compound in a substantially non-swellable diffusion matrix,wherein the matrix is formed with respect to its essential releasecharacteristics by ethylcellulose and at least one fatty alcohol.

It has surprisingly been found that only formulations having a(substantially) non-swellable diffusion matrix based on ethylcelluloseand at least one fatty alcohol ensure a sustained, invariant and, ifseveral active compounds are present, independent release of the activecompounds.

The inventive matrix formulation which is stable over long storageperiods permanently ensures that the active compounds are alwaysreleased in predetermined percentages and that the release rates do notinfluence each other. For combination preparations that e.g. compriseopioid analgesics and the respective antagonists, abuse of themedicaments, which presupposes that the agonist can be selectivelyextracted from the formulation, is prevented.

The formulation according to the invention disables selective extractionof the agonist from the preparation without the corresponding amount ofthe antagonist, regardless of the absolute and relative amount ofagonist and antagonist chosen. Furthermore, such preparations reduceside-effects which usually occur during the application of opioids.Since the active compounds are released from the same matrix, asimplified and more efficient production process is made possible. Thisalso applies for combination preparations comprising other compoundsother than opioids analgesics or antagonists thereof.

Moreover, the inventive formulation of a medicament ensures that givenidentical relative amounts, the active compounds show the same releaseprofiles regardless of the absolute amount present. Such independentrelease behaviour provides the physician with a wide range of usableabsolute amounts of the active compounds, where the optimal compoundratio (e.g. for opioid agonist/antagonist ratios) is known. It is thuspossible to comfortably adjust the dosage for each individual patient,either by increasing the dosage gradually or, if necessary, by reducingthe dosage gradually. This ability to adjust the dosage for theindividual patient is extremely useful from a medical point of view, asis the increased compliance.

The inventive formulations also allow for the production ofpharmaceutical preparations that release active compounds of differentstructures with the same release profiles.

Since the pre-determinable release of active compounds from theinventive formulation does not change regardless of the amount and thenumber of compounds and takes place from the same matrix, once acombination of active compounds has been established preparations withdifferent amounts of active compound can be produced without significanttechnical effort and corresponding preparations for differenttherapeutically relevant areas may be provided.

The characterizing features of the present invention are the sustained,invariant, and if several active compounds are present, independentrelease of the active compounds from a non-swellable (at least not to anextent which is relevant for the release) diffusion matrix with thematrix being determined with respect to its essential releasecharacteristics by ethylcellulose and at least one fatty alcohol and theactive compounds remaining stable over long storage periods.

According to the present invention “sustained” or “controlled sustainedrelease” or “retardation” means that pharmaceutically active substancesare released from a medicament over a longer period of time than is thecase with known formulations for immediate release. Preferably, therelease takes place over a time period of two to twenty-four hours, oftwo to twenty hours, especially preferably over a time period of two tosixteen hours or two to twelve hours, with the specifications satisfiing legal requirements.

In the context of the present invention, “sustained release” does notmean that the active compounds are released from the formulation or themedicament in a pH-dependent manner. According to the invention, theterm “sustained release” refers to the release of active compounds froma medicament over an extended period of time. It does not imply thecontrolled release at a defined place; it therefore does not mean thatthe active compounds are either released only in the stomach, or only inthe intestine. Correspondingly, the release of the active compounds fromthe inventive formulations occurs preferably pH-independently. (Ofcourse, a pH dependent release at a defined place could individually beachieved by, e.g. enteric coating of the medicament, although thispresently seems not to be advantageous).

According to the invention, “independent release” means that, given thepresence of at least two active compounds, a change of the absoluteamount of one compound does not influence the release profiles of theother compounds so that the release profiles of the other compounds arenot changed. For formulations according to the invention such anindependent release behaviour is independent of the pH value, for whichthe release is measured, or of the production process. The pHindependency particularly applies to the acidic range, i.e. for pHvalues<7. The release profile (or release behaviour) is defined as thechange of the release of the active compound from the formulation withtime, with the amount of each active compound released provided inpercents of the total amount of the active compound. The release profileis determined by known tests.

Specifically, this means that for example the release profile ofoxycodone, as it is observed for an oxycodone/naloxone-combination with12 milligrams oxycodone and 4 milligrams naloxone, does not change, if acorresponding preparation with the same formulation contains 12milligrams oxycodone, but 6 milligrams naloxone.

The independent release feature preferably refers to the situation wherepreparations of substantially equal composition are compared for therelease profile. Preparations of substantially equal composition havedifferent amounts of the active compounds but are otherwise basicallythe same with respect the components of the composition whichessentially influence the release behaviour.

If e.g. the above-mentioned preparations are compared (with the firstpreparation comprising 12 mg oxycodone and 4 mg naloxone and the secondpreparation comprising 12 mg oxycodone and 6 mg naloxone) bothpreparations, provided that they have the same total weight, willprovide for the same release profile for oxycodone and naloxone if thedifference in the naloxone amount is replaced by a component in theformulation that typically does not influence the release behaviour. Asshown in the Example section, the difference in the amount of naloxonemay be replaced by a typical pharmaceutically inert filler such aslactose without changing the release profiles.

The person skilled in the art is well aware that if the amount of theactive compound in which two preparations differ is replaced by asubstance that is essential for the release behaviour of theformulation, such as ethylcellulose or a fatty alcohol, differences inthe release behaviour may occur. Thus, the independent release featurepreferably applies to formulations that have different amounts of theactive compounds but are otherwise identical or at least highly similarwith respect to the components that essentially influence the releasebehaviour (given that formulations of the same total weight arecompared). According to the invention, “invariant release behaviour” or“invariant release profile” is defined so that the percentage of theabsolute amount of each active compound released per time unit does notsignificantly change and remains sufficiently constant (and thus doesnot substantially change) if absolute amounts are changed. Sufficientlyconstant percentages mean that the percentage released per time unitdeviates from a mean value by not more than 20%, preferably by not morethan 15% and especially preferably by not more than 10%. The mean valueis calculated from six measurements of the release profile. Of course,the amount released per time unit has to satisfy the legal andregulatory requirements.

Specifically, this means for example that given an oxycodone/naloxonecombination of 12 mg oxycodone and 4 mg naloxone, during the first 4hours 25% oxycodone and 20% naloxone are released. If theoxycodone/naloxone combination instead contains 24 mg oxycodone and 8 mgnaloxone, during the first 4 hours also 25% oxycodone and 20% naloxonewill be released. In both cases the deviation will not be more than 20%from the mean value (which in this case is 25% oxycodone and 20%naloxone).

As outlined for the independent release behaviour, the invariant releasefeature also preferably refers to a situation where preparations ofsubstantially equal composition are compared. Such preparation differwith respect to the amount of the active compounds, but are of the sameor at least highly similar composition with respect to therelease-influencing components of the preparation. Typically, thedifference in the amount of an active compound will be replaced by theamount of a pharmaceutical inert excipient which does not substantiallyinfluence the release behaviour of the preparation. Such apharmaceutical excipient may be lactose, which is a typical filler inpharmaceutical preparations. The person skilled in the art is well awarethat the invariant release feature may not apply to preparations wherethe difference in the amount of an active compound is replaced bysubstances that are known to essentially influence the release behaviourof the preparation, such as ethylcellulose or fatty alcohols.

In the Example section it is set out that if one preparation comprises20 mg oxycodone and 1 mg naloxone or 20 mg oxycodone and 10 mg naloxone,with the difference in naloxone being replaced by lactose, that the twopreparations of identical weight provide for the same release profiles,so that they exhibit a sustained, invariant and independent releasebehaviour.

According to the invention “storage stable” or “storage stability” meansthat upon storage under standard conditions (at least two years at roomtemperature and usual humidity) the amounts of the active compounds of amedicament formulation do not deviate from the initial amounts by morethan the values given in the specification or the guidelines of thecommon Pharmacopoeias. According to the invention, storage stabilityalso means that a preparation produced according to the invention can bestored under standard conditions (60% relative humidity, 25° C.) as itis required for admission to the market.

According to the invention, “storage stable” or “time stable” also meansthat after storage under standard conditions the active compounds showrelease profiles as they would upon immediate use without storage.According to the invention, the admissible fluctuations with respect tothe release profile are characterized in that the amount released pertime unit fluctuates by no more than 20%, preferably no more than 15%and especially preferably no more than 10%, with respect to a meanvalue. The mean value is calculated from six measurements of the releaseprofile. The term “storage stable” refers to the active compound as wellas to the other components within the inventive formulation andtherefore also to the formulation as a whole.

Preferably, the release of the active compounds from a sustained releaseformulation is determined by the Basket Method according to USP at pH1.2 or pH 6.5 with HPLC.

Storage stability is preferably determined by the Basket Methodaccording to USP at pH 1.2 with HPLC.

According to the invention, the term “formulation” refers to thepreparation of a pharmaceutically active substance with additives(formulation aids) with the aim of enabling an optimal release,distribution and development of activity of the active compound for therespective applications.

According to the invention, a “non-swellable” or “substantiallynon-swellable” diffusion matrix is a matrix formulation for which therelease of the active compounds is not influenced (or at least not to arelevant degree) by swelling of the matrix (particularly in thephysiological fluids of the relevant target sites in the patient'sbody).

According to the invention, the term “substantially non-swellable”diffusion matrix also refers to a matrix whose volume will increase byapproximately 300%, preferably by approximately 200%, more preferably byapproximately 100%, by approximately 75% or by approximately 50%, evenmore preferably by approximately 30% or by approximately 20% and mostpreferably by approximately 15%, by approximately 10%, by approximately5% or by approximately 1% in aqueous solutions (and particularly in thephysiological fluids of the relevant target sites in the patient'sbody).

It has now surprisingly been found that formulations for medicamentswith a substantially non-swellable diffusion matrix allow for asustained, invariant and, where several compounds are present,independent release of the active compounds, when the diffusion matrixcomprises ethylcellulose as the matrix-scaffold-forming substance and ismoreover determined with respect to its essential releasecharacteristics by ethylcellulose and/or at least one fatty alcohol.Additionally, such formulations are characterized by good storagestability. Given the present knowledge, mainly formulations with such adiffusion matrix allow to release the active compounds in theaforementioned inventive manner. Formulations with a (substantially)swellable diffusion matrix or an erosive matrix are currently notconsidered to be suitable for that.

Therefore, water-swellable substances and particularly water-solublepolymers may generally not be used as scaffold-forming substances forthe production of matrices for formulations in accordance with theinvention. Particularly, common matrix-forming polymers such aspolyvinylpyrridone, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxymethylcellulose, poly(vinylalcohols), alginates, hydratedhydroxyalkylcellulose and hydroxypropylmethylcelluloseether arecurrently not considered to be suitable for the production offormulations in according with the invention.

Scaffold-forming substances that can form non-swellable diffusionmatrices may be used for the production of formulations in accordancewith the invention if they provide for a release behaviour of the activecompound in accordance with the invention, i.e. for a sustained,invariant and, where several components are present, independentrelease, as well as for storage stability of the formulation.Water-insoluble polymers, that are commonly used for the production ofmatrix-based sustained release pharmaceutical preparations may also notbe used straightforwardly for the production of formulations inaccordance with the invention. Common scaffold-forming substances suchas acrylic acid and methacrylic acid copolymers, methylnethacrylatecopolymers, ethoxyethylmethacrylate copolymers, cyanoethylmetha-crylate,aminoalkylmethacrylate copolymers, poly(acrylic acid), poly(methacrylicacid), polymethacrylates, poly(methylmethacrylate) copolymers,polyacrylamine or alginic acid are currently not considered to besuitable for the production of formulations in accordance with theinvention.

Matrices which are based on polymethacrylates (as e.g. Eudragit® RS30Dand Eudragit® RL30D) or comprise relevant amounts of water-swellablematerial, particularly of hydroxyalkylcellulose such as HPMC willcurrently not be considered usable in accordance with the invention.

Currently, alkylcelluloses will generally also not be considered for theproduction of formulations in accordance with the invention.Propylcellulose e.g. is of too lipophilic character to produce matriceswith release characteristics in accordance with the invention.Methylcellulose is also not suitable for the formulations in accordancewith the invention.

In accordance with the invention, the matrix that ensures the sustainedrelease of the active compound will be selected in such a way that therelease of the active compounds takes place in a sustained, invariantand, if several compounds are present, independent manner, and that theformulation is storage stable. Preferably such matrices comprisepolymers based on ethylcellulose, with ethylcellulose being anespecially preferred polymer. Specifically preferred are matricescomprising polymers available on the market under the trademarkSurelease®. Particularly preferred is the use of Surelease® E-7-7050.

Other retardation methods, such as e.g. film coatings that ensure asustained release, are currently not considered to be suitable forproduction of formulations that provide for a release behaviour of theactive compounds which is in accordance with the invention. Furthermore,they are not considered to be suitable for production of formulationsthat ensure that the formulation is storage stable.

For formulations in accordance with the invention which comprise anon-swellable diffusion matrix on an ethylcellulose basis, the amount ofethylcellulose (or Surelease® E-7-7050) in the matrix will vary between1-15%, preferably between 3-12%, particularly preferably between 5-9%and even more preferably between 6-8%. The percentages indicating theamount of ethylcellulose (or Surelease®) with respect to the totalweight of the preparation.

Formulations in accordance with the preparation preferably comprise afatty alcohol as the second component which has a sustained releaseeffect besides ethylcellulose. Fatty alcohols may comprise lauryl,myristyl, stearyl, cetylstearyl, ceryl and/or cetylalcohol. Preferably,stearyl and/or cetylalcohol will be used. The amount of fatty alcoholin.the matrix will be between 5-30%, preferably between 10-25% andparticularly preferably between 15-20%. Particularly preferred is anamount of fatty alcohol of substantially 20% (if the matrix is producedby spray granulation) or of substantially 18% (if the matrix is producedby extrusion). All percentages indicating the amount of fatty alcoholrefer to the total weight of the preparation.

Formulations with release behaviour according to the invention comprisein particular matrices comprising ethylcellulose and at least one fattyalcohol as the components that essentially influence the releasecharacteristics of the matrix. The amount of ethylcellulose and the atleast one fatty alcohol may vary significantly, so that preparationswith different release profiles may be achieved. Even though theinventive preparations will usually comprise both of the aforementionedcomponents, in some cases it may be preferred that the preparationscomprise only ethylcellulose or the fatty alcohol(s) as the releasedetermining components.

Formulations in accordance with the invention may comprise furthercomponents which have a sustained release effect if required. However,it has to be ensured that the release of the active compounds from theformulation and the storage stability of the formulation are inaccordance with the invention and are not negatively influenced. Suchadditional components with sustained release effect may comprisepolyalkylene glycols and particularly preferably polyethylene glycols.

According to the invention, formulations that provide a release of theactive compounds in accordance with the invention may comprise, besidesthe matrix forming polymers, fillers and additional substances, such asgranulating aids, lubricants, dyes, flowing agents and plasticizers.

Lactose, glucose or saccharose, starches and their hydrolysates,microcrystalline cellulose, cellactose, sugar alcohols such as sorbitolor mannitol, poorly soluble calcium salts like calciumhydrogenphosphate,dicalcium- or tricalciumphosphate may be used as fillers.

Povidone may be used as granulating aid.

Highly-disperse silica (Aerosil®), talcum, corn starch, magnesium oxideand magnesium- and/or calcium stearate may preferably be used as flowingagents or lubricants.

Magnesium stearate and/or calcium stearate can preferably be used aslubricants. Fatty acids like stearic acid, or fats like hydrated castoroil can also preferably be used.

Polyethylene glycols and fatty alcohols like cetyl and/or stearylalcohol and/ or cetostearyl alcohol can also be used as additionalsubstances that influence retardation.

Other pharmaceutically acceptable excipients which are known in the art,such as surfactants, conserving agents, diluents, granulating aids,colorants, aromatic compounds, detergents, buffers and/or anti-stickingagents may also be comprised in the sustained release matrix, if theformulation still provides for a release behaviour in accordance withthe invention, i.e. a sustained, invariant and, if several compounds arepresent, independent release. Such formulations also have to providegood storage stability of the active compounds within the matrix.

If fillers and additional substances such as dyes and the mentionedlubricants, flowing agents and plasticizers are used, care has to betaken that according to the invention only such combinations togetherwith the matrix forming substance and/or the matrix forming substancesare used, which ensure release profiles of the active compounds inaccordance with the invention.

All these additional components of the formulations will be chosen insuch a way that the release matrix receives the character of asubstantially non-water- or non-buffer-swellable and non-erosivediffusion matrix.

According to the invention, a formulation is especially preferred thatcomprises ethylcellulose or Surelease® E-7-7050 as a matrix-buildingsubstance, stearyl alcohol as fatty alcohol, magnesium stearate aslubricant, lactose as filler and povidone as a granulating aid.

Matrices that are in accordance with the invention can be used toproduce preparations that release active compounds in a sustained,independent and invariant manner and that release equal amounts of theactive compounds per time unit. Specifically, this means that in thecase of a oxycodone/naloxone combination containing 12 mg oxycodone und4 mg naloxone, 25% oxycodone and 25% naloxone are released within thefirst 4 hours. Correspondingly, in the case of a oxycodone/naloxonecombination containing 24 mg oxycodone and 8 mg naloxone, 25% oxycodoneand 25% naloxone are released during the first 4 hours, with thedeviation in both cases being no more than 20% of the mean value (whichin this case is 25% oxycodone or naloxone).

Such an equal release behaviour for both active compounds may bedesirable for medical aspects.

A preferred embodiment of the invention relates to preparations thatrelease 1% to 40%, preferably 5% to 35%, more preferably between 10% and30% and even more preferably between 15% and 25% of oxycodone and/ornaloxone after 15 minutes. In other preferred embodiments of theinvention, 15% to 20%, 20% to 25%, approximately 15%, approximately 20%or approximately 25% of oxycodone and/or naloxone are released after 15minutes.

Another preferred embodiment of the invention relates to preparationsthat release between 25% to 65%, preferably between 30% to 60%, motepreferably between 35% to 55% and even more preferably between 40% to50% of oxycodone and/or naloxone after one hour. Preferred embodimentsof the invention also relate to preparations that release between 40% to45%, 45% to 50%, approximately 40%, approximately 45% or approximately50% of oxycodone and/or naloxone after one hour.

Yet another preferred embodiment of the invention relates topreparations that release between 40% to 85%, preferably between 45% to80%, more preferably between 45% to 75% and even more preferably between45% to 55%, 50% to 60%, 55% to 65%, 65% to 75% or 75% to 85% ofoxycodone and/or naloxone after 2 hours. Preferred embodiments alsocomprise preparations that release approximately 45%, approximately 50%,approximately 55%, approximately 60%, approximately 65%, approximately70%, approximately 75%, approximately 80% or approximately 85% ofoxycodone and/or naloxone after 2 hours.

One preferred embodiment of the invention relates to preparations thatrelease 60% to 100%, preferably between 75% to 95%, more preferablybetween 80% to 95%, and even more preferably between 80% to 90% ofoxycodone and/or naloxone after 4 hours. Preferred embodiments of theinvention also relate to preparations that release between 80% to 85%,85% to 90%, approximately 80%, approximately 85% or approximately 90% ofoxcodone and/or naloxone after 4 hours.

One preferred embodiment of the invention also relates to preparationsthat release between 65% to 100%, preferably between 75% to 100%, morepreferably between 80% to 95% and even more preferably between 80% to85%, between 85% to 90% or between 90% to 95% of oxycodone and/ornaloxone after 7 hours. Preferred embodiments of the invention alsorelate to preparations that release approximately 80%, approximately85%, approximately 90% or approximately 95% of oxycodone and/or naloxoneafter 7 hours.

Yet another preferred embodiment of the invention relates topreparations that release between 85% to 100%, preferably between 90% to100%, more preferably between 95% to 100% and even more preferablyapproximately 95% or 100% of oxycodone and/or naloxone after 12 hours.

Preparations in accordance with the invention can be produced as allcommon application forms which, on principle, are suitable forretardation formulations and which ensure that the active compounds arereleased in a manner in accordance with the invention. Especiallysuitable are tablets, multi-layer tablets and capsules. Additionalapplication forms like granules or powders can be used, with only thoseapplications forms being admissible that provide a sufficientretardation and a release behaviour in accordance with the invention.

Pharmaceutical preparations may also comprise film coatings. However, ithas to be ensured that the film coatings do not negatively influence therelease properties of the active compounds from the matrix and thestorage stability of the active compounds within the matrix. Such filmcoatings may be colored or may comprise a initial dosage of the activecompounds if required. The active compounds of this initial dosage willbe immediately released so that the therapeutically effective bloodplasma level is reached very quickly. It has to be ensured that, bycoating the preparations in accordance with the invention, the releasebehaviour of the active compounds is not negatively influenced.

The active compounds that are comprised within the formulation inaccordance with the invention and which are released in a sustained,invariant and, if several compounds are present, independent manner fromthe inventive matrix and which are also storage stable within thematrix, are not limited to a special class of compounds.

Pharmaceutically active compounds according to the present inventionthus comprise antipyretic, analgesic and anti-inflammatory agents suchas indomethacin, aspirin, diclofenac, ibuprofren, antiulcer agents suchas sulpiride, coronary vasodilaters such as nifedipine, peripheralvasodilators such as ifenprodil tartrate, antibiotics such asampicillin, chloramphenicol or erythromycin, synthetic antimicrobialagents such as nalidixic acid, antispasmodic agents such aspropantheline bromide, antitussive and antiasthmatic agents such astheophylline or aminophylline, bronchodilators such as diprophylline,diuretics such as furosemide, muscle relaxants such as chlorophenesincarbamate, cerebral metabolism improving agents such meclofenoxatehydrochloride, minor tranquilizers such as oxazolam, diazepam orclotiazepam, major tranquilizers such as sulpiride, beta-blockers suchas pindolol, antiarrhythmic agents such as procainamide hydrochloride,anticoagulants such as ticlopidine hydrochloride, antiepileptics such asphenytoin, antihistaminics such as chlorpheniramine maleate, antiemeticssuch as difenidol hydrochloride, antihypertensive agents suchdimethylaminoethyl reserpilinate hydrochloride, sympathomimetic agentssuch as dihydroergotamine mesilate, expectorants such as bromhexinehydrochloride, oral antidiabetic agents such as glibenclamide,cardio-vascular system drugs such as ubidecarenone, iron preparationssuch as ferrous sulfate, non stearoidal anti-inflammatory drugs orvitamins. Particularly preferred are analgesics comprising the group ofopiates and opioids such as oxycodone, morphine, dihydrocodeine,oxymorphine, buprenorphine or tramadol. Also preferred are analgesicantagonists such as naltrexone or naloxone. Other opioid agonists andantagonists can be found, e.g. in WO 99/32119.

Particularly preferred are formulations in accordance with the inventionthat comprise opioid analgesics (opioid agonists) and/or opioidantagonists as pharmaceutically active compounds.

According to the invention, opioid analgesics or opioid agonistscomprise all compounds that belong to class NO2A of opioid analgesicsaccording to the ATC Classification of the WHO, and that display ananalgesic effect upon application in accordance with the invention.Preferably, an opioid agonist is selected from the. group of morphine,oxycodone, hydromorphone, propoxyphene, nicomorphine, dihydrocodeine,diamorphine, papaveretum, codeine, ethylmorphine, phenylpiperidine andderivates thereof, methadone, dextropropoxyphene, buprenorphine,pentazocine, tilidine, tramadol, hydrocodone. Further examples foruseable analgesics according to the invention are meperidine,oxymorphone, alphaprodine, anileridine, dextromoramide, metopone,levorphanol, phenazocine, etoheptazine, propiram, profadol,phenampromide, thiambuten, pholcodeine, codeine, dihydrocodeinon,fentanyl,3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-A′-cyclohexen,3-dimethylamino-0-(4-methoxyphenyl-carbamoyl)-propiophenone oxime,(−)β-2′-hydroxy-2, 9-dimethyl-5-phenyl-6, 7-benzomorphane,(−)2′-hydroxy-2-(3-methyl-2-butenyl) -9-methyl-5-phenyl-6,7-benzomorphane, pirinitramide, (−) α-5,9-diethyl-2′ hydroxy-2-methyl-6,7-benzomorphane, ethyl1-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-3-methyl-4-oxo-6-phenyl-indol-2-carboxylate,1-benzoylmethyl-2, 3-dimethyl-3- (m-hydroxy-phenyl) -piperidine,N-allyl-7α (1-R-hydroxy-l -methylbutyl)-6,14-endo-ethanotetrahydronororipavine,(−)2′-hydroxy-2-methyl-6,7-benzomorphane, noracylmethadol,phenoperidine, α-d1-methadol, α-1-methadol, β-d1-acetylmethadol,α-1-acetylnethadol and β-1-acetylmethadol. These lists are not to beunderstood as exclusive.

Especially preferred analgesically effective opiod agonists areoxycodone, hydrocodone, hydromorphone, morphine, codeine,dihydrocodeine, methadone, oxymorphone, fentanyl and sufentanyl.Specifically, the opioid agonist is oxycodone.

According to the invention, antagonists comprise such compounds thatcounteract opioid agonists (as defined earlier). Such compounds can alsobe found in the ATC Classification of the WHO. According to theinvention, compounds are preferred that upon application in accordancewith the invention decrease the side effects , the habituation effectsand the addictive potential caused by the opioid agonists. Antagonistscan comprise among others, naltrexone, naloxone, nalmefene, nalorphine,nalbuphine, naloxoneazinen, methylnaltrexone, ketylcyclazocine,norbinaltorphi inine, naltrindol, 6-β-naloxol and 6-β-naltrexol.

Especially preferred antagonists comprise naltrexone, nalmefene andnaloxone. Specifically preferred as an antagonist is naloxone.

According to the invention, formulations with a combination of oxycodoneas agonist and naloxone as antagonist are particularly preferred. Theagonist is preferably in excess compared to the antagonist. The excessof the agonist is defmed based on the amount of the unit dosage of theantagonist present in the combination preparation. The extent of theexcess of the opioid agonist is usually given in terms of the weightratio of agonist to antagonist.

In the case of oxycodone and naloxone, preferred weight ratios ofagonist to antagonist lie within a weight ratio range of 25:1 atmaximum, especially preferred are the weight ratio ranges 15:1, 10:1,5:1, 4:1, 3:1, 2:1 and 1:1.

The absolute amounts of agonist and antagonist to be used depend on thechoice of the active compounds. According to the invention, care has tobe taken that agonist and antagonist are released from thepharmaceutical preparation that has been formulated for sustainedrelease, only in an independent and invariant manner.

If oxycodone and naloxone are used for a combination preparation,preferably between 10 and 150 mg, especially preferably between 10 and80 mg of oxycodone (typical amounts for use) and preferably between 1and 50 mg naloxone per unit dosage are used.

In other preferred embodiments of the invention, the preparations maycomprise between 5 and 50 mg of oxycodone, between 10 and 40 mg ofoxycodone, between 10 and 30 mg of oxycodone or approximately 20 mg ofoxycodone. Preferred embodiments of the invention may also comprisepreparations with between 1 and 40 mg naloxone, 1 and 30 mg naloxone, 1and 20 mg naloxone or between 1 and 10 mg naloxone per unit dosage.

According to the invention, the ratio between oxycodone and naloxone hasto be chosen in such a way that release profiles for both activesubstances in accordance with the invention are guaranteed and that theagonist can display its analgesic effect while the amount of theantagonist is chosen in such a way that habituation- oraddiction-promoting effects and side effects of the agonist are reducedor abolished, without (substantially) affecting the analgesic effect ofthe agonist. According to the invention, development of habituation andaddiction as well as obstipation and breath depression are to beconsidered as side effects of analgesically effective opioid agonists.

Even though this might not be expressly stated, the term “agonist” or“antagonist” always comprises pharmaceutical acceptable and equallyacting derivatives, salts and the like. If, for example, oxycodone ornaloxone is mentioned, this also comprises, besides the free base, theirhydrochloride, sulfate, bisulfate, tatrate, nitrate, citrate,bitratrate, phosphate, malate, maleate, hydrobromide, hydrojodide,fumarate, succinate and the like.

According to the invention, agonists and antagonists are formulated in away that they are released from the resulting pharmaceutical preparationin a sustained, independent and invariant manner. This does not meanthat the antagonist is in excess compared to the agonist. On thecontrary, it is preferred that in formulations comprising anagonist/antagonist combination, that show a release profile inaccordance with the invention, the agonist is in excess compared to theantagonist.

Preparations produced according to the invention can be applied orally,nasally, rectally and/or by inhalation for use in pain therapy.According to the invention, parenteral application is not envisaged.Especially preferred is a formulation for oral application.

Formulations in accordance with the invention may be produced byembedding the active compound into the matrix by e.g. melting,spray-freezing, spray-drying, granulating, direct tabletting and/orextrusion. Pharmaceutical preparations or preliminary stages thereofwhich are in accordance with the invention can be produced by build-upor break-down granulation. A preferred embodiment is the production byspray granulation with subsequent drying of the granules. Anotherpreferred embodiment is the production of granules by build-upgranulation in a drum or on a granulating disk. The granules may then bepressed into e.g. tablets using appropriate additional substances andprocedures.

The person skilled in the art is familiar with granulating technology asapplied to pharmaceutical technology. The embodiment examples (seebelow) disclose specific embodiments of the invention. However, it iswell within the scope of the person skilled in the art to adapt theparameters of the process in order to achieve specific purposes.

The pharmaceutical formulations in accordance with the invention orprecursors thereof may be advantageously produced by extrusion (insteadof granulation), since several working steps (such as the drying of thegranulates during spray-granulation) may be omitted, so thatformulations in accordance with the invention may be producedefficiently and with less cost.

As production of formulations in accordance with the invention byextrusion is a continuous process, several working steps can be omitted(in comparison to other production methods, such as spray-granulation),leading to more efficient production of the formulations in accordancewith the invention.

For production of formulations in accordance with the invention byextrusion Surelease®.

E-7-7050, which comprises dibutylsebacat as plasticizer and additionalother components may be omitted and ethylcellulose may be directly used,resulting in a cheaper and more efficient production process.

Production of pharmaceutical preparations or preliminary stages thereof,which are in accordance with the invention, by extrusion technology isespecially advantageous. In one preferred embodiment, pharmaceuticalpreparations or preliminary stages thereof are produced by meltextrusion with co- or counter-rotating extruders comprising two screws.Another preferred embodiment is the production by means of extrusion,with extruders comprising one or more screws. These extruders may alsocomprise kneading elements.

Extrusion is also a well-established production process inpharmaceutical technology and is well known to the person skilled in theart. The person skilled in the art is well aware that during theextrusion process, various parameters, such as the feeding rate, thescrew speed, the heating temperature of the different extruder zones (ifavailable), the water content, etc. may be varied in order to produceproducts of the desired characteristics. The Example section providesfor numerous examples of preparations according to the invention thathave been produced by extrusion.

The aforementioned parameters will depend on the specific type ofextruder used. For production of formulations in accordance with theinvention, extrusion may be performed with one or multiple screwextruders which may be counter-rotating or co-rotating screws. Thefeeding rate of the components is dependent on the specific extrudertype.

The aforementioned parameters will depend on the specific type ofextruder used. During extrusion the temperature of the heating zones, inwhich the components of the inventive formulation melt, may be between40 to 120° C., preferably between 50 to 100° C., more preferably between50 to 90° C., even more preferably between 50 to 70° C. and mostpreferably between 50 to 65° C., particularly if counter-rotating twinscrew extruders (such as a Leistritz Micro 18 GGL) are used. The personskilled in the art is well aware that not every heating zone has to beheated. Particularly behind the feeder where the components are mixed,cooling at around 25° C. may be necessary. The screw speed may varybetween 100 to 500 revolutions per minute (rpm), preferably between 100to 250 rpm, more preferably between 100 to 200 rpm and most preferablyaround 150 rpm, particularly if counter-rotating twin screw extruders(such as a Leistritz Micro 18 GGL) are used. The geometry and thediameter of the nozzle may be selected as required. The diameter of thenozzle of commonly used extruders typically is between 1 to 10 mm,preferably between 2 to 8 mm and most preferably between 3 to 5 mm. Thedifferent extruders may differ with respect to their set up and comprisee.g. kneading elements. The ratio of length versus diameter of the screwof extruders that may be used for production of inventive preparationsis typically around 40:1.

Typical screw profiles which may be used in the production offormulations according to the invention by extrusion are shown in FIGS.1A and 1B. Extrusion procedures for the production of pharmaceuticalpreparations which show a sustained release are well known to the personskilled in the art.

In a preferred embodiment, a counter-rotating twin-screw extruder isused for the production of formulations in accordance with theinvention. This may be e.g. an extruder of the type Micro 18 GGL(Leistritz AG, Nürnberg, Germany). For this preferred embodiment theextruder has no kneading elements (see also FIG. 1A). The feeding rateof the components used for the production of the formulation inaccordance with the invention is between 1-3 kg/h, preferably between1-2 kg/h. Particularly preferred is a feeding rate of 1.5 kg/h. Thetemperature of the heating zones is between 40°-120° C., 50°-100° C.,preferably 50°-90° C., more preferably 50°-70° C. Particularly preferredare 50°-65° C. The extruder provides for 10 heating zones. In the firstheating zone the components are generally cooled around 25° C. Thetemperature in the other heating zones will then preferably be around50°-65° C. and may vary for every heating zone. The screw speed will bebetween 1-500 rpm, preferably between 1-250 rpm, more preferably between120-200 rpm and even more preferably around 150 rpm. The diameter of thenozzle will be between 1-10 mm, preferably between 2-8 mm, or between3-5 mm. In a particularly preferred embodiment of the invention, thediameter of the nozzle is approximately 3 mm.

Generally, the temperatures of the heating zones have to be selectedsuch that no temperatures develop that may destroy the pharmaceuticallyactive compounds. The feeding rate und screw speed will be selected suchthat the pharmaceutically active compounds are released from thepreparations produced by extrusion in a sustained, independent andinvariant manner and are storage stable in the matrix. If e.g. thefeeding rate is increased, the screw speed may have to be increasedcorrespondingly to ensure the same retardation.

The person skilled in the art knows that all the aforementionedparameters depend on the specific production conditions (extruder type,screw geometry, number of components etc.) and may have to be adaptedsuch that the preparations produced by extrusion provide for asustained, independent and invariant release as well as for theafore-mentioned storage stability. The person skilled in the art knowshow to properly adjust the aforementioned parameters

The person skilled in the art can infer from the Examples (see below)that by changing the parameters during extrusion and by changing thecomposition with respect to the compounds that are substantiallyresponsible for the release behaviour of the preparations, preparationswith different release profiles may be obtained. Thus, the presentinvention allows to first produce a preparation with a desired releaseprofile for oxycodone and naloxone or naloxone alone by e.g. varying theamount of fatty alcohols or the matrix-forming polymer ethylcellulose aswell as production parameters such as temperature, screw speed (duringextrusion) or pressure power during tablet production.

Once a preparation with the desired release profile has been obtained,the inventive preparations according to the invention allow the personskilled in the art to change the amounts of the preparations withrespect to the active compounds as outlined above. Preparationscomprising different amounts of the active compounds but of otherwisesubstantially equal composition, however, will then provide for thefeatures of sustained, invariant and independent release.

The Example section therefore discloses numerous examples showing thatpreparations with different release profiles may be obtained by changingthe amount of e.g. ethylcellulose. Other examples show that once apreparation has been established with desired release profiles, thechange in the amount of naloxone will not influence the releasebehaviour of such preparations if the difference in the amount of theactive compound is replaced by pharmaceutically inert excipients such aslactose.

The production of formulations in accordance with the invention byextrusion is preferred with the formulations comprising opioidanalgesics and opioid antagonists as active compounds. Particularlypreferred is the production of formulations in accordance with theinvention that comprise oxycodone and naloxone, wherein the preferredweight ratios of agonist to antagonist are within a weight ratio rangingfrom maximal 25:1, preferably of 20:1, 15:1, 10:1, 5:1, 2:1 and 1:1.

A preferred embodiment of the invention refers to a preparation thatcomprises the inventive matrix and naloxone as the pharmaceuticallyactive compound. Such preparations may be advantageously used for avariety of different indications.

Preparations according to the invention comprising an opioid antagonistsuch as naloxone as the pharmaceutically active compound may e.g. beused for complete or partial treatment of opioid-induced side effects.Such side effects may comprise dizziness, breath depression,opioid-abuse, development of tolerance and addiction and particularlyobstipation.

Preparations according to the invention which comprise naloxone as apharmaceutically active compound preferably are used for the treatmentof opioid-induced obstipation. Almost 90% of patients under opioidtreatment show signs of obstipation which may be responsible for otheradditional ailments such as discomfort, tension and pain in the abdomen,nausea and emesis, anorexia, haemorrhoids, anal fissures, fecalincontinence, paradoxic diarrhoea, urine retention, intestinal pseudoobstruction, and decubitus of the colon which may lead to perforation(Neuenschander et. al. (2002), Palliativmedizin auf einen Blick,Schweizerische Krebsliga).

So far opioid-induced obstipation has been treated by the application oflaxatives. However, application of typical laxatives does not allow forthe simultaneous treatment of other opioid-induced side effects .

The advantage of the use of inventive preparations comprising naloxoneis that the inventive preparations allow for a sustained release of theantagonist naloxone. If e.g. patients in pain are treated simultaneouslywith opioid analgesics, application of such preparations comprisingnaloxone will allow for a long term treatment of opioid-induced sideeffects including obstipation. Particularly, the application of naloxoneas a sustained release formulation should allow for an efficienttreatment of opioid-induced obstipation. At the same time it is ensuredthat there is no tolerance development towards opioid analgesics ifapplied simultaneously. Moreover, the use of naloxone does not lead toany disturbances in the water and electrolyte metabolism and does notinduce colon irritation.

The provision of a sustained release formulation comprising naloxone asthe only pharmaceutical active agent compound also has the advantagethat patients that are treated with opioid analgesics may receive adosis of naloxone which is sufficient to counteract the opioid-inducedside effects without leading to a significant reduce of analgesia. Withinventive preparations being available which comprise different amountsof naloxone, one has the possibility to specifically treat patients inneed of pain treatment that receive different amounts of opioid agonistsor are treated with different opioid agonists

Yet another preferred embodiment of the invention relates to the use ofinventive preparations comprising naloxone for treatment ofopioid-induced pruritus. Opioid-induced puritus is one of the sideeffects that is experienced by the patients as extremely unpleasant.

In another embodiment of the invention, preparations comprising naloxonemay also be used for treatment of idiopathic syndromes such asidiopathic pruritus or pruritus due to cholestasia and/or renaldysfunction. These preparations may also be used for the treatment ofchronic idiopathic obstipation or irritable bowel syndrome. Thus,preparations in accordance with the invention comprising naloxone as apharmaceutically active compound may be used for a multitude oftherapeutic indications and purposes which may be either opioid-inducedor not. As the inventive preparations provide for a sustained andreproducibly invariant release behaviour, they allow for an efficienttreatment of the aforementioned syndromes.

In a preferred embodiment preparations in accordance with the inventioncomprising naloxone as the active compound release 30% to 60%,preferably 35% to 55%, more preferably 40% to 50% and even morepreferably 40% to 45% or 45% to 50% of naloxone after 90 minutes. Inanother preferred embodiment of the invention, preparations comprisingnaloxone release approximately 40%, approximately 45% or approximately50% of the active compound after 90 minutes.

In another preferred embodiment preparations in accordance with theinvention comprising naloxone release 30% to 70%, preferably 35% to 65%and more preferably between 40% to 60% of naloxone after 120 minutes. Inyet another embodiment of the invention, preparations comprisingnaloxone release preferably between 35% to 40%, 40% to 45% and 45% to50% of naloxone after 120 minutes. In another preferred embodiment ofthe invention the preparations comprising naloxone release approximately35%, approximately 40%, approximately 45%, approximately 50% orapproximately 55% of naloxone after 120 minutes.

In another preferred embodiment preparations in accordance with theinvention comprising naloxone release 55% -90%, preferably 60% to 80%,more preferably 65% to 75% and even more preferably 65% to 70% or 70% to75% of naloxone after 420 minutes. In yet another preferred embodimentof the invention, preparations comprising naloxone release approximately65%, approximately 70% or approximately 75% of naloxone after 420minutes.

In another preferred embodiment preparations in accordance with theinvention comprising naloxone release 60% to 90%, preferably 65% to 85%,more preferably 70% to 80% and even more preferably 75% to 80% ofnaloxone after 600 minutes. In yet another preferred embodiment of theinvention, preparations comprising naloxone release approximately 75%,approximately 80% or approximately 85% of naloxone after 600 minutes.

Examples that display highly advantageous embodiments of the inventionare set out below. Examples are also given showing that formulationswhich are in accordance with the invention differ mainly in theirstructure from formulations with a sustained release which has beenproduced by using commonly used scaffold-forming polymers. Only theformulations produced in accordance with the invention provide for asustained, invariant and, if several compounds are present, independentrelease of the active compounds with the formulation being storagestable. The examples are not to be interpreted as limiting the possibleembodiments of the invention.

EXAMPLE 1 Production of Tablets with Different Oxycodone/NaloxoneAmounts in a Non-Swellable Diffusion Matrix by Spray Granulation

The following amounts of the listed components were used for theproduction of oxycodone/naloxone tablets according to the invention.Preparation (designation) Oxy/Nal-0 Oxy/Nal-5 Oxy/Nal-10 oxycodone HCl20.0 mg 20.0 mg 20.0 mg naloxone HCl — 5.0 mg 10.0 mg Lactose Flow 59.25mg 54.25 mg 49.25 mg Lac 100 Povidone 30 5.0 mg 5.0 mg 5.0 mgSurelease ® 10.0 mg solid 10.0 mg solid 10.0 mg solid material materialmaterial Stearyl alcohol 25.0 mg 25.0 mg 25.0 mg Talcum 2.5 mg 2.5 mg2.5 mg Mg-Stearate 1.25 mg 1.25 mg 1.25 mg

The Surelease® E-7-7050 polymer mixture used had the followingcomposition. Surelease ® Ethylcellulose 20 cps DibutylsebacateAmmoniumhydroxide Oleic acid Siliciumdioxide Water

For the production of tablets oxycodone HCl, naloxone HCl, Povidone 30and Lactose Flow Lac 100 were mixed in a tumbling mixer (Bohle) andsubsequently spray-granulated with Surelease® E-7-7050 in a fluidizedbath granulating device (GPCG3). The material was sieved over a Comill1.4 mm sieve. An additional granulation step was carried out with meltedfatty alcohol in a high-shear mixer (Collette). All tablet coresproduced by this approach had a weight of 123 mg, based on drysubstance.

EXAMPLE 2 Production of Tablets with Oxycodone and Naloxone in aNon-Swellable Diffusion Matrix by Extrusion

The following amounts of the listed components were used for theproduction of the oxycodone/naloxone tablets according to the invention.Preparation (designation) Oxy/Nal-Extr oxycodone HCl 20 mg naloxone HCl10 mg Kollidon 30 6 mg Lactose Flow Lac 100 49.25 mg Ethylcellulose 45cpi 10 mg Stearyl alcohol 24 mg Talcum 2.5 mg Mg-Stearate 1,25 mg

The listed amounts of oxycodone HCl, naloxone HCl, ethylcellulose 45cpi, Povidone 30, stearyl alcohol and Lactose Flow Lac 100 were mixed ina tumbling mixer (Bohle). This mixture was subsequently extruded with acounter-rotating twin screw extruder of the type Micro 18 GGL (LeistritzAG, Nürnberg, Germany). The temperature of heating zone 1 was 25° C., ofheating zone 2, 50° C., of heating zones 3 to 5, 60° C., of heatingzones 6 to 8, 55° C., of heating zone 9, 60° C. and of heating zone 10,65° C. The screw rotating speed was 150 revolutions per minute (rpm),the resulting melt temperature was 87° C, the feed rate was 1.5 kg/h andthe diameter of the nozzle opening was 3 mm. The extruded material wassieved with a Frewitt 0.68×1.00 mm sieve. The grinded extrudate was thenmixed with talcum and magnesium stearate that had been added over a 1 mmhand sieve and was subsequently pressed into tablets. The extruder has ascrew geometry, as shown in FIG. 1A.

In comparison to the oxycodone/naloxone tablets which also have theSurelease®-based non-swellable diffusion matrix produced by spraygranulation (see Example 1), extruded preparations comprise lesscomponents.

EXAMPLE 3 Release Profile of the Oxycodone/Naloxone Tablets from Example1

The release of the active compounds was measured over a time period of12 hours, applying the Basket Method according to USP at pH 1.2 usingHPLC. Tablets Ox/Nal-0, Ox/Nal-5 and Ox/Nal-10 were tested.

One recognizes from FIG. 2 and the values listed in the Table that inthe case of a non-swellable diffusion matrix based on Surelease®, therelease rates of different oxycodone amounts, independent of thenaloxone amount, remain equal (invariant). Correspondingly, invariantrelease profiles are observed for naloxone at different oxycodoneamounts. Ox/ Time Ox/Nal-0 Ox/Nal-5-O Ox/Nal-5-N Ox/Nal-10-O Nal-10-N(min) Oxy Oxy Nal Oxy Nal 0 0 0 0 0 0 15 26.1 24.9 23.5 22.8 24.1 12062.1 63 61 57.5 60.2 420 91.7 94.5 91.9 89.4 93.5 720 98.1 99.6 96.695.7 100.6

The release values refer to oxycodone or naloxone (line 2) and are givenas percentages. The mean value for the release of naloxone at e. g. 420min is 92,7%. The maximal deviation at 420 min is 1%. Oxy and Nal standfor oxycodone and naloxone and indicate the active compound which hasbeen measured.

EXAMPLE 4 Release Profile of Oxycodone/Naloxone Tablets from Example 2at Different pH-Values

The release of active compounds from the tablets was measured over atime period of 12 hours at pH 1.2 or for 1 hour at 1.2 and subsequentlyfor 11 hours at pH 6.5. Release rates were determined by the basketmethod according to USP using HPLC.

The following release rates were measured for 12 hours at pH 1.2: TimeOxy/Nal-Extr-1,2-O Oxy/Nal-Extr-1,2-N (min) Oxy Nal 0 0 0 15 24.1 24.0120 62.9 63.5 420 92.9 93.9 720 96.9 98.1

The following release rates were measured for 1 hour at pH 1.2 and 11hours at pH 6.5: Time Oxy/Nal-Extr-6,5-O Oxy/Nal-Extr-6,5-N (min) OxyNal 0 0 0 60 48.1 49.2 120 65.0 64.7 240 83.3 81.8 420 94.1 92.3

The release rates refer to oxycodone and naloxone (line 2) and are givenas percentages. Oxy and Nal stand for oxycodone and naloxone andindicate the active compound measured.

The comparison of the values given in the Tables of Example 4 and theTable of Example 3 make clear that independent of the productionprocess, active compounds are released in equal amounts from thepreparations. For example, 89.4% of oxycodone is released fromspray-granulated tablets (Ox/Nal-10-tablets, see Example 3) at 420minutes, while 92.9% is released from extruded tablets(Oxy/Nal-Extr-1.2-O, Example 4) at 420 minutes. The release of oxycodonefrom extruded tablets thus deviates by 1.1% from the mean value of therelease of oxycodone from spray-granulated tablets (91.9% at 420minutes). 93.5% of naloxone is released from spray-granulated tablets(Ox/Nal-10-tablets, see Example 3) at 420 minutes, while 93.9% isreleased from extruded tablets (Oxy/Nal-Extr.-1.2-O, Example 4) at 420minutes. The release of naloxone from extruded tablets thus deviates by1.3% from the mean value of the release of naloxone fromspray-granulated tablets (92.7% at 420 minutes).

Moreover, one can infer from a comparison of the values of the Tables ofExample 4 and from FIGS. 3A and 3B that independent of the pH value atwhich the release rates have been measured the release of oxycodone andnaloxone remain equal and invariant.

EXAMPLE 5 Comparative Example Release Behaviour of Valoron® Tablets

The release of the active substances from tablets was monitored over atime period of 7 hours. Valoron® tablets with 50 mg tilidine and 4 mgnaloxone (Ti/Nal-50/4) or 100 mg tilidine and 8 mg naloxone(Ti/Nal-100/8) or 150 mg tilidine and 12 mg naloxone (Ti/Nal-150/12)were tested by the Basket Method according to USP for 1 h at pH 1.2 andthen for additional 6h at pH 6.5 using HPLC.

One recognizes from FIGS. 4A and 4B and the values listed in the Tablethat in case of a swellable (and possibly erosive) diffusion matrix withrelevant amounts of HPMC, the release of different amounts of tilidinevaries significantly and is not invariant for different amounts ofnaloxone. This applies in turn to naloxone. This means that for this pHthe release of the active compounds is not independent of each other.Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Ti/Nal- Time 50/4-T 50/4-N100/8-T 100/8-N 150/12-T 150/12-N (min) Til Nal Til Nal Til Nal 0 0 0 00 0 0 60 37.2 27.6 33.9 27.3 29.9 23.3 120 47.6 31.7 46.5 33.4 41.5 28.5180 54.7 37.4 55 41.2 48.2 35 240 59.7 44 68.2 59.5 54.5 40.1 300 65.250.6 82.6 72.9 60.5 47.5 360 70.3 58 85.7 82.7 67.2 56.4 420 74.2 60.893.1 90.9 84.9 78.9

The release values refer to tilidine or naloxone (line 2) and are givenas percentages. The mean value for the release of naloxone at e. g. 420min is 78,87%. The maximal deviation at 420 min is 20,4%. Til und Nalstand for tilidine and naloxone and indicate the active compound tested.

EXAMPLE 6 Structure Comparison of Tablets of Examples 1 and 2 withValoron® N Tablets by Electron Microscopy

For electron microscopy tablets were used that comprised 20 mg oxycodoneand 10 mg naloxone and were produced either by spray granulationaccording to Example 1 (Ox/Nal-10) or by extrusion according to Example2 (Oxy/Nal-Extr). Additionally, a Valoron® N tablet with 100 mg Tilidinand 8 mg Naloxone was used. FIGS. 5A and 5B show differentmagnifications of scanning electron microscopy pictures of aOx/Nal-10-tablet with a formulation according to the invention which wasproduced by spray granulation. FIGS. 6A and 6B show differentmagnifications of scanning electron microscopy pictures of aOxy/Nal-Extr-tablets with a formulation according to the invention,which was produced by extrusion. FIGS. 7A and 7B show scanning electronmicroscopy pictures of the Valoron® N-tablet.

From a comparison of the figures one can clearly see that tablets with aformulation according to the invention have a surface which issubstantially finer and more homogeneously structured and which showsfewer cracks than the Valoron® tablet, regardless of whether the tabletshave been produced by spray granulation or extrusion. The structuraldifference is possibly the reason for the different release behavioursof the different preparations.

EXAMPLE 7 Production of Tablets Comprising Different Amounts of Naloxoneand Different Matrices by Spray Granulation

The following amounts of the listed components were used for theproduction of naloxone tablets: Preparation (designation) Nal-5-EudNal-5-Sure Nal-10-Sure naloxone HCl 5.0 mg 5.0 mg 10.0 mg Lactose Flow74.25 mg 74.25 mg 69.25 mg Lac 100 Povidone 30 5.0 mg 5.0 mg 5.0 mgEUDRAGIT ® 10 mg solid — — RS 30D material Surelease ® — 10 mg solid 10mg solid material material Triacetin 2.0 mg — — Stearyl alcohol 25.0 mg25.0 mg 25.0 mg Talcum 2.5 mg 2.5 mg 2.5 mg Mg-Stearate 1.25 mg 1.25 mg1.25 mg

EUDRAGIT® 30 D can be purchased from Röhm GmbH, Darmstadt. Surelease®can be purchased from Colorcon Ltd., Idstein.

EUDRAGIT® RS 30 D or. Surelease® -Polymer mixtures of the followingcompositions were used: EUDRAGIT ® RS 30 D Surelease ®Ammoniomethacrylate copolymer B Ethylcellulose 20 cps Sorbic acidDibutylsebacate Natriumhydroxide Ammoniumhydroxide Water Oleic acidSiliciumdioxide Water

For the production of tablets, naloxone HCl, Povidone 30 and LactoseFlow Lac 100 were mixed in a tumbling mixer (Bohle) and subsequentlyspray-granulated with EUDRAGIT® RS 30 D or Surelease® in a fluidizedbath granulating device (GPCG3). An additional granulation step wascarried out with melted fat alcohol in a high-shear mixer (Collette).All tablet cores produced by this approach had a weight of 125 mg,referred to the dry substance.

EXAMPLE 8 Production of Tablets with Naloxone in a Non-SwellableDiffusion Matrix by Extrusion

The following amounts of the listed components were used for theproduction of naloxone tablets according to the invention. Preparation(designation) Nal-Extr naloxone HCl 10 mg Lactose Flow Lac 100 70.25 mgKollidone 30 5 mg Ethylcellulose 45 cpi 8 mg Stearyl alcohol 26.0 mgTalcum 2.5 mg Mg-Stearate 1.25 mg

The listed amounts of naloxone HCl, ethylcellulose 45 cpi, Kollidone 30,stearyl alcohol and Lactose Flow Lac 100 were mixed in a tumbling mixer(Bohle). This mixture was subsequently extruded with a counter-rotatingtwin screw extruder of the type Micro 18 GGL (Leistritz AG, Nürnberg,Germany). The temperature of heating zone 1 was 25° C., of heating zone2, 50° C., of heating zones 3 to 10, 55° C. The screw rotating speed was140 rpm, the resulting melt temperature was 65° C., the feed rate was1.25 kg/h and the diameter of the nozzle opening was 3 mm. The extrudedmaterial was sieved with a Frewitt 0.68×1.00 mm sieve. The grindedextrudate was then mixed with talcum and magnesium stearate that hadbeen added over a 1 mm hand sieve and was subsequently pressed intotablets. The extruder has a screw geometry, as shown in FIG. 1.

In comparison to the oxycodone/naloxone tablets which also have theSurelease®-based non-swellable diffusion matrix produced by spraygranulation (see Example 7), extruded preparations comprise lesscomponents.

EXAMPLE 9 Release Behaviour of Naloxone Tablets from Example 7

The release of the active compound was measured over a time period of 16hours, applying the Basket Method according to USP at pH 1.2 using HPLC.Two tablets (designated A and B) of Nal-5-Eud, Nal-5-Sure andNal-10-Sure were tested.

One recognizes from FIG. 8A and 8B and the values listed in the Tablethat in the case of a non-swellable diffusion matrix based onSurelease®, the release rates of naloxone independent of the absoluteamount reproducibly do not change and remain substantially equal(invariant). This does not apply for the release of naloxone from matrixbased on Eudragit®. Time Nal-5- Nal-5- Nal-5- Nal-5- Nal-10- Nal-10-(min) Eud-A Eud-B Sure-A Sure-B Sure-A Sure-B 0 0 0 0 0 0 0 15 18.4818.23 23.86 21.97 20.65 22.25 90 40.46 26.15 46.74 47.33 45.18 45.98 24062.43 53.47 70.48 69.49 69.13 68.76 420 82.9 72.27 91.04 88.69 88.0687.5 720 97.46 85.74 100.62 99.1 96.05 95.74 960 107.6 96.26 102.26102.33 97.91 97.43

The release values refer to naloxone and are given as percentages. Themean value for the release of naloxone in the case of e.g. Nal-Suretablets at 90 min is 46.3%. The maximal deviation at 90 mnin is 2.2%.The mean value at this time point for Nal-Eud tablets is 33.3% and thedeviation is 21.5%.

EXAMPLE 10 Release Behaviour of Naloxone Tablets from Example 8

The release of the active compound was measured for different tabletsover a time period of 12 hours, applying the Basket Method according toUSP at pH 1.2 using HPLC.

One recognizes from FIG. 9 and the values listed in the Table that therelease of naloxone independent of the production process reproduciblydoes not change when tablets have been produced by extrusion. Zeit (min)Nal-Extr-A Nal-Extr-B Nal-Extr-C 0 0 0 0 15 15 15 14.3 120 40.7 41.940.1 420 72 75.2 73.6 720 90.1 92.4 91.2

The release values refer to naloxone and are given as percentages. Themean value for the release of naloxone in the case of Nal-Extr tabletsat 120 min is 40.9%. The maximal deviation at 120 min is 2.4%.

EXAMPLE 11 Structure Comparison of Naloxone Tablets of Examples 7 and 8

For electron microscopy, Nal-Eud tablets according to Example 7 with 5mg (Nal-5-Eud) as well as a Nal-Extr tablets according to Example 8.

FIGS. 10A and 10B show different magnifications of scanning electronmicroscopy pictures of a Nal-5-Eud tablet. FIGS. 11A and 11B showdifferent magnifications of scanning electron microscopy pictures of aNal-Extr tablets with a formulation in accordance with the invention.

From a comparison of the figures, one can clearly see that theformulation in accordance with the invention has a surface which issubstantially finer and more homogeneously structured. Particularly, inFIGS. 10A and 10B naloxone blooms can be seen, but not in FIGS. 11A and11B. This structural difference is possibly the reason for the differentrelease behaviour of the different preparations.

EXAMPLE 12 Structure Comparison of Naloxone Granulates of Examples 7 and8

For electron microscopy, granulates as they were used for production ofNal-Sure tablets according to Example 7 witt 10 mg naloxone(Nal-10-Sure) and Nal-Extr tablets according to Example 8 were used.

FIGS. 12A and 12B show different magnifications of scanning electronmicroscopy pictures of Nal-10-Sure granulates. FIGS. 13A and 13B showdifferent magnifications of scanning electron microscopy pictures of aNal-Extr granulates with a formulation in accordance with the invention.

One can clearly see that independent of the production processgranulates with a formulation in accordance have homogeneouslystructured surfaces without major cracks or blooms. Without wanting tobe bound to a scientific theory it is assumed that the surfacecharacteristics are responsible for the release behaviour of theformulations in accordance with the invention.

EXAMPLE 13 Storage Stability of Naloxone Tablets Depending on the MatrixUsed

Multiple tablets comprising either EUDRAGIT® RS 30 D or Surelease® and 5mg naloxone were produced as described in Example 1. The tablets werestored at 25° C. and 60% relative humidity. At different time points,the release behaviour was tested as described in Example 4.

As can be recognized from FIGS. 4A and 4B and the Tables, the releaseprofiles of naloxone tablets having been formulated with EUDRAGIT® RS 30D, differ already after a short time of storage. In contrast, therelease profile of tablets which have been formulated with Surelease®are almost invariant, even after 15 months of storage. Storage time(Months) 0 1 3,5 Preparation (designation) Nal-5- Nal-5- Nal-5- Time(min) Eud-0 Eud-1 Eud-3,5 15 16.46 12.66 15.06 90 30.29 28.78 30.6 24052.94 43.85 47.5 480 71.07 57.37 62.86 720 83.29 66.68 73.58 1020 91.6173.03 80.97

Storage time (Months) 0 3 6 15 Preparation (designation) Nal-5- Nal-5-Nal-5- Nal-5- Time (min) Sure-0 Sure-3 Sure-6 Sure-15 15 21.58 22.5216.04 24.36 120 49.94 49.05 51.93 55.59 420 79.83 86.32 87.99 88.49 72091.74 97.55 100.27 97.09

In the Table, the release rates are given in percentages. In each case,the release of naloxone was tested.

EXAMPLE 14 Production of Tablets with Different Oxycodone/NaloxoneAmounts in a Non-Swellable Diffusion Matrix by Extrusion

The following amounts of the listed components were used for theproduction of oxycodone/naloxone tablets according to the invention.Preparation (designation) OxN20/ OxN20/ OxN20/ OxN20/ 1-Extr-A 1-Extr-B1-Extr-C 10-Extr-A Oxycodone   20 mg   20 mg   20 mg   20 mg HClNaloxone HCl    1 mg    1 mg    1 mg   10 mg Lactose Flow 58.25 mg 58.25mg 58.25 mg 49.25 mg Lac 100 Kollidon ® 30    6 mg    6 mg    6 mg    6mg Ethylcellulose   10 mg   10 mg   10 mg   10 mg Stearly alcohol   24mg   24 mg   24 mg   24 mg Talcum  1.25 mg  1.25 mg  1.25 mg  1.25 mgMg-Stearate  2.5 mg  2.5 mg  2.5 mg  2.5 mg

Extrusion was performed as described above (Example 2) with thefollowing parameters: OxN20/1-Extr-A: temperature: 55-63° C. rpm(screw): 150 rpm feeding rate: 1.5 kg/h OxN20/1-Extr-B: temperature:55-63° C. rpm (screw): 155 rpm feeding rate: 1.5 kg/h OxN20/1-Extr-C:temperature: 55-63° C. rpm (screw): 1505 rpm feeding rate: 1.5 kg/hOxN20/10-Extr-A: temperature: 55-63° C. rpm (screw): 160 rpm feedingrate: 1.75 kg/h

Tablet production was performed with a common tabletting device with thefollowing parameters: OxN20/1-Extr-A: rpm: 40 rpm Pressure power: 9 kNOxN20/1-Extr-B: rpm: 42 rpm Pressure power: 8.9 kN OxN20/1-Extr-C: rpm:36 rpm Pressure power: 9 kN OxN20/10-Extr-A: rpm: 36 rpm Pressure power:7.5 kN

The release of the active compounds was measured over a time period of12 hours, applying the Basket Method according to USP at pH 1.2 usingHPLC. Tablets OxN20/1-Extr-A, OxN20/1-Extr-B, OxN20/1-Extr-C andOxN20/10-Extr-A were tested.

One recognizes from the values listed in the Table that in the case of anon-swellable diffusion matrix based on ethylcellulose, the releaserates of different naloxone amounts, independent of the oxycdone amount,remain substantially equal. Correspondingly, the preparations providefor an independent and invariant release of the active compounds.OxN20/1- OxN20/1- OxN20/1- OxN20/10- Time Extr-A Extr-B Extr-C Extr-A(min) Oxy Nal Oxy Nal Oxy Nal Oxy Nal 0 0 0 0 0 0 0 0 0 15 21.2 25.821.7 21.1 19.7 19.3 23.3 24.3 120 56.6 53.8 58.8 57.3 57.7 56.2 64.566.9 420 87.2 84.5 94.2 92.6 93.7 91.5 92.7 96.3 720 99.7 96.8 100.1 98100.6 97.5 93.6 97.4

The release values refer to oxycodone or naloxone (line 2) and are givenas percentages. The mean value for the release of naloxone at e. g. 420min is 92.3%. The maximal deviation at 420 min is 7.4%. Oxy and Nalstand for oxycodone and naloxone and indicate the active compound whichhas been measured.

Thus, once a preparation with the desired release profile has beendeveloped, one can change the amount of the active compounds withoutsignificantly changing the release profiles of the active compounds. Thepreparations comprising different amounts of the active compounds stillprovide for a sustained, independent an invariant release of the activecompounds.

EXAMPLE 15 Production of Tablets with Oxycodone/Naloxone in aNon-Swellable Diffusion Matrix by Extrusion

In the following example it is set out that using formulations accordingto the present invention, preparations comprising oxycodone and naloxonewith particular release behaviours may be obtained.

The following amounts of the listed components were used for theproduction of oxycodone/naloxone tablets according to the invention.Preparation OxN20/1- OxN20/1- OxN20/10- OxN20/10- OxN20/10- OxN20/10-(designation) Extr-D Extr-E Extr-B Extr-C Extr-D Extr-E oxycodone HCl 20mg 20 mg 20 mg 20 mg 20 mg 20 mg naloxone HCl 1 mg 1 mg 10 mg 10 mg 10mg 10 mg Lactose Flow 56.25 mg 56.25 mg 54.25 mg 65.25 mg 60.25 mg 55.25Lac 100 Kollidon ® 30 7 mg 6 mg 6 mg 7.25 mg 7.25 mg 7.25 mgEthylcellulose 11 mg 12 mg 10 mg 12 mg 12 mg 12 mg Stearyl alcohol 24 mg24 mg 24 mg 28.75 mg 28.75 mg 28.75 mg Talcum 1.25 mg 1.25 mg 1.25 mg1.25 mg 1.25 mg 1.25 mg Mg-Stearate 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg2.5 mg

Extrusion was performed as described above (Example 2) with thefollowing parameters: OxN20/1-Extr-D: temperature: 55-63° C. rpm(screw): 150 rpm feeding rate: 1.5 kg/h OxN20/1-Extr-E: temperature:55-63° C. rpm (screw): 150 rpm feeding rate: 1.5 kg/h OxN20/10-Extr-B:temperature: 55-63° C. rpm (screw): 160 rpm feeding rate: 1.75 kg/hOxN20/10-Extr-C: temperature: 55-63° C. rpm (screw): 160 rpm feedingrate: 1.75 kg/h OxN20/10-Extr-D: temperature: 55-63° C. rpm (screw): 150rpm feeding rate: 1.5 kg/h OxN20/10-Extr-E: temperature: 55-63° C. rpm(screw): 150 rpm feeding rate: 1.5 kg/h

Tablet production was performed with a common tabletting device with thefollowing parameters: OxN20/1-Extr-D: rpm: 39 rpm Pressure power: 11 kNOxN20/1-Extr-E: rpm: 39 rpm Pressure power: 10.5 kN OxN20/10-Extr-B:rpm: 36 rpm Pressure power: 9.5 kN OxN20/10-Extr-C: rpm: 36 rpm Pressurepower: 7.8 kN OxN20/10-Extr-D: rpm: 39 rpm Pressure power: 9 kNOxN20/10-Extr-E: rpm: 39 rpm Pressure power: 7.5 kN

The release of the active compounds was measured over a time period of12 hours, applying the Basket Method according to USP at pH 1.2 usingHPLC. Tablets OxN20/1-Extr-D, OxN20/1-Extr-E, OxN20/10-Extr-B,OxN20/10-Extr-C, OxN20/10-Extr-D and OxN20/10-Extr-E were tested.OxN20/1- OxN20/1- OxN20/10- OxN20/10- OxN20/10- OxN20/10- Time Extr-DExtr-E Extr-B Extr-C Extr-D Extr-E (min) Oxy Nal Oxy Nal Oxy Nal Oxy NalOxy Nal Oxy Nal 0 0 0 0 0 0 0 0 0 0 0 0 0 15 16.6 16.2 17.4 17.2 26.126.8 21.8 21.9 18.5 18.2 18.4 18.2 120 47.6 46.9 49.6 49.7 71.1 73.061.2 61.8 52.8 52.8 53.3 53.3 420 82.7 84.5 84.6 85.7 94.3 96.6 93.294.7 86.3 86.3 87.2 88.2 720 95 97 95.2 95.8 94.9 97.9 96.4 97.9 94.894.8 95.7 96.5

The release values refer to oxycodone or naloxone (line 2) and are givenas percentages. Oxy and Nal stand for oxycodone and naloxone andindicate the active compound which has been measured.

The example shows that preparations with particular release profiles maybe produced if ethylcellulose and fatty alcohols are used as thematrix-components that essentially influence the release characteristicsof the preparations. Once a preparation with desired releasecharacteristics has been obtained the amount of the active compounds maybe changed. The preparations will still provide for a sustained,independent and invariant release behaviour (see example 14).

EXAMPLE 16 Production of Tablets with Naloxone in a Non-SwellableDiffusion Matrix by Extrusion

The following amounts of the listed components were used for theproduction of naloxone tablets according to the invention. Preparation(designation) N10-Extr-1 N10-Extr-2 N10-Extr-3 N10-Extr-4 N10-Extr-5N10-Extr-6 Naloxone HCl 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg Lactose Flow69.25 mg 69.25 mg 69.25 mg 69.25 mg 69.25 mg 69.25 mg Lac 100 Povidone30 5.0 mg 5.0 mg 5.0 mg 5.0 mg 5.0 mg 5.0 mg Ethylcellulose 10 mg 10 mg10 mg 10 mg 10 mg 10 mg Stearyl alcohol 25 mg 25 mg 25 mg 25 mg 25 mg 25mg Talcum 1.25 mg 1.25 mg 1.25 mg 1.25 mg 1.25 mg 1.25 mg Mg-Stearate2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg

Extrusion was performed as described above with the followingparameters: N10-Extr-1: temperature: 55-63° C. rpm (screw): 120 rpmfeeding rate: 1.5 kg/h N10-Extr-2: temperature: 55-63° C. rpm (screw):140 rpm feeding rate: 1.5 kg/h N10-Extr-3: temperature: 55-63° C. rpm(screw): 160 rpm feeding rate: 1.75 kg/h N10-Extr-4: temperature: 55° C.rpm (screw): 120 rpm feeding rate: 1.75 kg/h N10-Extr-5: temperature:55-55° C. rpm (screw): 140 rpm feeding rate: 1.5 kg/h N10-Extr-6:temperature: 55° C. rpm (screw): 160 rpm feeding rate: 1.5 kg/h

Tablet production was performed with a common tabletting device with thefollowing parameters: N10-Extr-1 rpm: 39 rpm Pressure power: 11.6 kNN10-Extr-2: rpm: 39 rpm Pressure power: 12.5 kN N10-Extr-3: rpm: 39 rpmPressure power: 11.6 kN N10-Extr-4: rpm: 36 rpm Pressure power: 14.5 kNN10-Extr-5: rpm: 36 rpm Pressure power: 15.0 kN N10-Extr-6: rpm: 36 rpmPressure power: 15.0 kN

The release of the active compound was measured over a time period of 12hours, applying the Basket Method according to USP at pH 1.2 using HPLC.Tablets N10-Extr-A, N10-Extr-B, N10-Extr-C, N10-Extr-D, N10-Extr-E andN10-Extr-F were tested.

One recognizes the values listed in the Table that, in the case of anon-swellable diffusion matrix based on ethylcellulose and a fattyalcohol, the release rates of naloxone remain substantially equal(invariant). Time N10- N10- N10- N10- N10- N10- (min) Extr-1 Extr-2Extr-3 Extr-4 Extr-5 Extr-6 0 0 0 0 0 0 0 15 13.0 12.9 13.0 13.2 13.313.5 120 37.4 37.6 37.9 37.6 37.9 38.7 420 67 67.3 67.9 67.5 67.4 69.5600 78.1 78.5 78.7 78.4 78.3 80.5

The release values refer to naloxone and are given as percentages. Themean value for the release of naloxone at e. g. 420 min is 67.8%. Themaximal deviation at 420 min is 2.5%.

1. Storage stable pharmaceutical formulation comprising at least twopharmaceutically active compounds in a diffusion matrix, characterizedin that the matrix is determined with respect to its essential releasecharacteristics by ethylcellulose or an ethylcellulose-based polymer andat least one fatty alcohol and that the active compounds are releasedfrom the substantially non-swellable diffusion matrix in a sustained,invariant and independent manner.
 2. Pharmaceutical formulation to claim1, characterized in that the fatty alcohol comprises lauryl, myristyl,stearyl, cetylstearyl, ceryl and/or cetylalcohol.
 3. Pharmaceuticalformulation to claim 2, characterized in that the formulation comprisesethylcellulose.
 4. Pharmaceutical formulation according to claim 3,characterized in that the formulation does not comprise relevant amountsof alkaline and/or water-swellable substances.
 5. Pharmaceuticalformulation according to claim 4, characterized in that the formulationcomprises fillers, lubricants, flowing agents and/or plasticizers. 6.Pharmaceutical formulation according to claim 5, characterized in thatthe fillers are selected from the group comprising sugars, starches andhydrolysates thereof, sugar alcohols, poorly soluble calcium saltsand/or povidone.
 7. Pharmaceutical formulation according to claim 5,characterized in that it comprises magnesium stearate, calcium stearateand/or calcium laureate and/or fatty acids.
 8. Pharmaceuticalformulation according to claim 5, characterized in that it comprises aflowing agent selected from the group consisting of highly dispersedsilica, talcum, corn starch, magnesium oxide, magnesium andcalciumstearate.
 9. Pharmaceutical formulation according to claim 5,characterized in that it comprises dibutyl sebacate as a plasticizer.10. Pharmaceutical preparation according to claim 5, characterized inthat the formulation can be stored over a period of at least two yearsunder standard conditions (60% relative humidity, 25° C.) in accordancewith admission guidelines.
 11. Pharmaceutical preparation according toclaim 5, characterized in that it comprises as the pharmaceuticallyactive compounds at least one opioid analgesic selected from the groupcomprising morphine, oxycodone, hydromorphone, propoxyphene,nicomorphine, dihydrocodeine, diamorphine, papaveretum, codeine,ethylmorphine, phenylpiperidine and derivatives thereof, methadone,dextropropoxyphene, buprenorphine, pentazocin, tilidine, tramadol andhydrocodone and at least one opioid antagonist, selected from the groupcomprising naltrexone, naloxone, nalmefene, nalorphine, nalbuphin,naloxonazinene, methylnaltrexone, ketylcyclazocine, norbinaltorphimine,naltrindol, 6-β-naloxol and 6-β-naltrexol.
 12. Pharmaceuticalformulation according to claim 11, characterized in that the opioidanalgesic and the antagonist are present in the form of theirpharmaceutically acceptable and equally active derivatives, free base,salts and the like.
 13. Pharmaceutical formulation according to claim12, characterized in that the formulation comprises oxycodone andnaloxone, and wherein oxycodone is present in an amount raging fromabout 10 mg to about 150 mg, and naloxone is present in an amountranging from about 1 mg to about 50 mg per unit dosage. 14.Pharmaceutical formulation according to claim 13, characterized in thatit comprises oxycodone and naloxone in a weight ratio ranging from about25:1, to about 1:1.
 15. Pharmaceutical formulation according to claim12, characterized in that it contains oxycodone and naloxone withoxycodone being present in an amount ranging from about 10 Mg to about150 mg, and naloxone is present in an amount ranging from about 1 mg toabout 50 mg.
 16. Pharmaceutical formulation according to claim 13,characterized in that the formulation is in the form of a tablet,preferably a multi-layered tablet, a capsule, a dragèe, a granulateand/or a powder.
 17. Pharmaceutical formulation according to claim 16,characterized in that the pharmaceutical preparation is suitable fororal, nasal and/or rectal application.
 18. Pharmaceutical formulationaccording to claim 16, characterized in that the formulation is producedby build-up and/or break-down granulation.
 19. Pharmaceuticalformulation according to claim 17, characterized in that the formulationis produced by extrusion.
 20. Storage stable pharmaceutical formulationcomprising at least two active compounds in a sustained release matrix,characterized in that the matrix is a substantially non-swellablediffusion matrix whose release characteristics are determined by amountsof ethylcellulose or an ethylcellulose-based polymer and at least onefatty alcohol as matrix components, and by extrusion or granulation ofthe matrix materials together with the amount of the active compoundsfor formulation of an active compound-containing matrix.
 21. Storagestable pharmaceutical formulation according to claim 20, wherein thediffusion matrix is a substantially non-erosive matrix.
 22. Storagestable pharmaceutical formulation according to claim 20, wherein thematrix material contains ethylcellulose.
 23. Storage stablepharmaceutical formulation according to claim 20, wherein the matrix isformed by extrusion.
 24. Storage stable pharmaceutical formulationhaving an effective amount of an opioid agonist and an opioid antagonistin a substantially non-swellable and non-erosive diffusion matrix, whoserelease characteristics are determined by amounts of ethylcellulose oran ethylcellulose-based polymer and at least one fatty alcohol. 25.Storage stable pharmaceutical formulation according to claim 24 havingan effective amount of oxycodone and naloxone, with oxycodone beingpresent in an amount ranging from about 10 mg to about 150 mg, andnaloxone is present in an amount ranging from about 1 mg to about 50 mgper unit dosage.
 26. Storage stable pharmaceutical formulation accordingto claim 24 having an effective amount of oxycodone and naloxone,wherein oxycodone and naloxone are present in a weight ratio rangingfrom about 25:1, to about 1:1.
 27. Method for producing a formulationaccording to claim 26, characterized in that production is effected bygranulation, preferably build-up and/or break-down granulation. 28.Method for producing a formulation according to claim 26, being anextrusion method, wherein counter-rotating or co-rotating single ormultiple screw extruders with/without kneading elements are used. 29.Method according to claim 28, being an extrusion method whereincounter-rotating twin-screw extruders are used.
 30. Method according toclaim 28, characterized in that the temperature of the heating zones ofthe extruders is from about 20° to about 120° C.
 31. Method according toclaim 28, characterized in that the diameter of the nozzle on theextruder is between about 1 mm to about 10 mm.
 32. Method according toclaim 28, characterized in that the resulting temperature in theextruder does not influence the stability of the active compounds. 33.Method of producing a pharmaceutical dosage form for the treatment ofopioid-induced side effects, characterized in that the pharmaceuticaldosage form comprises a pharmaceutical formulation according to claim 5.34. Method according to claim 33, characterized in that the preparationis used for treatment of opioid-induced obstipation.
 35. Method ofproducing a pharmaceutical dosage form for the treatment of idiopathicsyndromes, characterized in that the pharmaceutical dosage formcomprises a pharmaceutical formulation according to claim
 5. 36. Methodaccording to claim 35, characterized in that the preparation is used fortreatment of irritable bowel syndrome, treatment of idiopathic pruritusor pruritus due to cholestasia and/or renal dysfunction.
 37. Methodaccording to 33, characterized in that the matrix is a substantiallynon-swellable diffusion matrix whose release characteristics aredetermined by amounts of ethylcellulose or an ethylcellulose-basedpolymer and of at least one fatty alcohol.
 38. Method according to 37,characterized in that the preparation comprises from about 1 mg to about50 mg naloxone.
 39. Method according to claim 38, characterized in thatnaloxone is present in the form selected from the pharmaceuticallyacceptable and equally active derivatives the free base, salts and thelike.
 40. Method according to claim 39, characterized in that the matrixis produced by extrusion.
 41. A pharmaceutical formulation according toclaim 4, characterized in that the formulation does not compriserelevant amounts of derivatives of acrylic acid and/orhydroxyalkylcelluloses.
 42. A pharmaceutical formulation according toclaim 6, characterized in that the fillers are selected from the groupcomprising lactose, glucose, saccharose, micro-crystalline cellulose,cellactose, sorbitol, mannitol, calcium hydrogenphosphate,dicalciumphosphate, tricalciumphosphate and povidone.
 43. Apharmaceutical formulation according to claim 7, characterized in thatit comprises stearic acid.
 44. A pharmaceutical formulation according toclaim 12, characterized in that the opioid analgesic and the antagonistare present in the form of the hydrochloride, sulfate, bisulfate,tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate,hydrobromide, hydroiodide, fumarate or succinate.
 45. A pharmaceuticalformulation according to claim 13, characterized in that the formulationcomprises oxycodone and naloxone, and wherein oxycodone is present in anamount raging from about 10 mg to about 80 mg and naloxone is present inan amount ranging from about 1 mg to about 50 mg per unit dosage.
 46. Apharmaceutical formulation according to claim 14, characterized in thatit comprises oxycodone and naloxone in a weight ratio ranging from about5:1 to about 1:1.
 47. A storage stable pharmaceutical formulationaccording to claim 23, wherein the matrix is formed by melt extrusion.48. A storage stable pharmaceutical formulation according to claim 25having an effective amount of oxycodone and naloxone, with oxycodonebeing present in an amount ranging from about 10 mg to about 80 mg andnaloxone being present in an amount ranging from about 1 mg to about 50mg per unit dosage.
 49. A storage stable pharmaceutical formulationaccording to claim 26 having an effective amount of oxycodone andnaloxone, wherein oxycodone and naloxone are present in a weight ratioranging from about 5:1 to about 1:1.
 50. The method according to claim30, characterized in that the temperature of the heating zones of theextruders is from about 50° to about 70° C.
 51. The method according toclaim 31, characterized in that the diameter of the nozzle on theextruder is between about 3 mm to about 5 mm.
 52. The method accordingto claim 34, characterized in that the preparation is used for treatmentof opioid-induced pruritus.
 53. The method according to 38,characterized in that the preparation comprises from about 5 mg to about20 mg naloxone.
 54. The method according to claim 39, characterized inthat naloxone is present in the form of the hydrochloride, sulfate,bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate,maleate, hydrobromide, hydroiodide, fumarate or succinate.